G-proteins are intracellular molecular “switches” that transmit signals into the cell
by attaching to G protein-coupled receptors in the cell membrane. While at the University of Illinois at Chicago in the early 1990s, Hamm and her colleagues
solved the G-protein’s three-dimensional structure.

They also showed that a peptide, a piece of protein, could prevent the G-protein from
hopping on and off its receptor each time a signal came to the cell. This suggested that the switch for a single pathway, such as the one activated by thrombin,
could be disabled by blocking a specific G-protein.

“Maybe PAR signaling is different” in diabetes, Hamm says. “If we find
it’s so, could we direct a therapy that could be able to quiet down the platelets?”

Through their collaboration, Hamm and Santoro also
have found that the collagen and thrombin receptors influence each other’s activity. That, says Santoro, “suggests some very interesting
pharmacological interventions.”

Clot busters

Over-active clotting is not the only problem faced by people with diabetes and obesity.
They also seem to have a faulty blood thinning system.

Normally, there’s a whole series of natural anti-coagulants, including protein C and
antithrombin III, which circulate through the bloodstream and inhibit clot formation.

Another set of short-lived anti-coagulants generated by the
blood vessel lining include nitric oxide and prostacyclin. They inhibit platelet aggregation and dilate blood vessels, thereby improving blood
flow.

“Mother Nature must have been very concerned about the possibility that we would form clots inside our blood vessels because we have
several different mechanisms that prevent this,” Vaughan says. If the natural anti-coagulants fail to do their job, there’s a “back-up,”
called the fibrinolytic (clot-dissolving) system.

The king of the clot-dissolvers is plasmin, an enzyme that hacks apart the fibrin
mesh.

Produced in an inactive form, plasminogen, in the liver, it is “liberated” to do its work by other enzymes, called plasminogen
activators. These enzymes, in turn, are inhibited by proteins called plasminogen activator inhibitors.

Plasminogen activators like t-PA and their
inhibitors, notably PAI-1, thus maintain a balance between too much clotting and not enough. It’s a balance that’s all too easily tipped—in
favor of thrombosis.

For example, too much fat in the bloodstream (a characteristic of obesity) and too much glucose (the hallmark of diabetes) can
increase levels of PAI-1. So can activation of the renin-angiotensin-aldosterone system (RAAS), which regulates blood pressure.

“For a protein
that’s involved in regulating the clot-dissolving system, it’s rather puzzling to see how it’s influenced by a variety of different factors
that you would think have nothing to do with clotting or protection from clotting,” says Vaughan, who is internationally known for his research on the
fibrinolytic system. “All these things that get messed up in obesity and insulin resistance end up driving PAI-1 production.”